G-protein coupled receptors (GPCRs) and signal transduction pathways represent important specific targets for a variety of human diseases, ranging from the control of blood pressure, allergic response, hormonal disorders, to human cancer. We have recently identified a subfamily of prostate-specific G-protein coupled receptors (PSGRs). Although these specific receptors shares sequence homology with olfactory GPCRs in their seven putative transmembrane domains, the expression of PSGRs is highly restricted to the human prostate gland and is increased dramatically in human prostate cancers compared to matched normal tissues. Aberrant expression of PSGRs correlates well with prostate tumorigenesis, suggesting important roles of PSGRs in prostate cancer development and progression. However, how these prostate specific G-protein coupled receptors regulate prostate tumor progression is still not clear, and the signaling pathways and genes/proteins regulated by PSGRs have not been identified and characterized. Therefore, our long-term objectives are to understand the functions and signaling pathways of these PSGRs; and to determine whether PSGRs can be used as biomarkers in diagnosis and as molecular targets in the treatment of prostate cancers. We will test the hypothesis that overexpression of PSGRs will lead to the activation of specific growth signaling pathways to promote prostate tumor development and progression. Three specific aims are proposed in this grant application: 1) Determine the direct correlations of PSGR overexpression with prostate cancer development using orthotopic and transgenic mouse models; 2) Delineate the mechanism of action for prostate-specific G-protein coupled receptors in prostate cancer development and progression; 3) Determine the cooperative functions of PSGR overexpression and the loss of PTEN tumor suppressor gene in prostate tumor progression and metastasis. Results obtained from this study will provide information on the physiological functions of these prostate-specific G-protein coupled receptors in cancer development and progression and their potential uses as molecular targets in prostate cancer therapy.